Factors controlling the activity of HMG-CoA reductase, the key regulatory enzyme of sterol biosynthesis, are being examined along the following general lines of investigation. 1) The mechanism by which lipik inhibitors, such as oleic acid and oleoyl CoA, inhibit enzyme activity. The effect of preincubation with substrates in preventing the inhibition is being explored from the point of view that profound conformational changes take place in the presence of substrate. The nature of a cytosolic factor which readily releases the inhibition is also being investigated. 2) The regulation of the enzyme by phosphorylation and dephosphorylation is being investigated in intestinal mucosal and liver preparations. We will especially examine the role that bicarbonate ions play in facilitating phosphorylation of the enzyme. 3) In view of profound conformational changes induced by incubation with substrate, we will examine how this affects the antigenic characteristics of the enzyme. 4) We plan to explore the effect of modulators of HMG-CoA reductase activity on the synthesis of other polyisoprenoids in the cell, e.g., dolichols and ubiquinone, to determine how each of the major products of the polyisoprenoid pathways in the cell affect the activity of the enzyme of mevalonate synthesis.